Colon adenocarcinoma is a major cause of cancer mortality worldwide'. Colorectal cancer is the third most common and second leading cause of cancer death in the United States2. Sporadic colon adenocarcinomas initiate as adenomas and evolve through a progression of molecular, cellular and histologic changes3. While 5-year mortality rates have modestly declined over the last 3 decades4, there is still a need to identify new prognostic biomarkers and therapeutic targets for this disease. Currently, chemotherapy has significant therapeutic value but surgery is the only curative form of treatment5.
Ideal therapeutic targets should be causally associated with disease and amenable to designing therapeutic interventions; whereas ideal biomarkers should be easy to measure and have strong associations with clinical outcomes. MicroRNAs could match both criteria6-8.
MicroRNAs are 18-25 nucleotide, non-coding RNA molecules that regulate the translation of many genes9. Since their discovery10,11, they have been found to regulate a variety of cellular processes including apoptosis12-14, differentiation10,11,15 and cell proliferation16. MicroRNAs may also have a causal role in carcinogenesis6,17. MicroRNA expression levels are altered in most tumor types18,19, including colon tumors19-22. The microRNAs miR-15 and miR-16a are deleted or downregulated in the majority of chronic lymphocytic leukemias23. Experimental manipulation of specific microRNAs modulates tumor development in mouse model systems16,24-26. The prognostic potential of microRNAs has also been demonstrated for chronic lymphocytic leukemia7, lung cancer8 and neuroblastomas27.
Aberrant microRNAs expression may be causal to carcinogenesis, inhibiting specific microRNAs may have therapeutic implications. Modified antisense oligonucleotides can be designed to specifically inhibit microRNA function28. Antagomirs are one type of antisense oligonucleotide that has proven effective at inhibiting microRNA function in vivo in mice29. The ease of designing specific inhibitors of microRNA function makes them candidates for therapeutic targets.